Future studies proposed in this application will continue to explore hormonal abnormalities in depression, with a shift in focus from solely HPA axis hormones to include interactions between the gonadal hormone axis and the stress axis. Depression is a disorder with a strong predilection for women. Abnormalities of several hormonal axes particularly the adrenal (stress) and thyroid axes have been well documented in depressed women, but few studies have explored the hypothalamic pituitary gonadal (HPG) axis. The occurrence of sex bias in the expression of depressive illness after the onset of puberty, as well as anecdotal studies suggesting an association between mood and cyclic gonadal steroid changes suggest that gonadal axis hormones may modulate the onset and course of depression. Hormones of the hypothalamic pituitary adrenal (HPA) axis have been demonstrated to affect the hypothalamic pituitary gonadal axis, particularly the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. Hypothalamic amenorrhea, exercise induced amenorrhea and anorexia nervosa all demonstrate activation of the HPA axis accompanying the abnormalities in GnRH and LH secretion. This suggests that activation of the HPA axis is closely linked to abnormal GnRH secretion in humans. This project proposes to study the interactions between these two hormonal axes (stress and gonadal) to determine if depression in women is accompanied by abnormalities in reproductive axis hormones and if abnormalities in the reproductive axis are linked to abnormalities in the HPA axis, or if the two abnormalities can co-exist independently. To characterize baseline secretion in these two axes,l2 hour studies using 3 minute sampling will be conducted in depressed women to examine pulsatile secretion of the gonadal hormones (LH, FSH, estradiol and progesterone) as well as pulsatile secretion of the stress axis hormones (ACTH and cortisol). These data will be compared with data from control women matched for age and menstrual cycle day. In depressed women pulse frequency and amplitude of LH secretion will each be examined, as well as frequency and amplitude of ACTH and cortisol pulses. GnRH secretion, as assessed by LH secretion in the periphery, appears to be the most sensitive index of disruptions in HPG axis secretion, but gonadal steroid hormones will also be evaluated. HPA axis pulsatility data will determine if secretory drive in depressed women increases in the zenith and nadir of the circadian rhythm, and if the onset of circadian driven secretory episodes shift in depressed women. In normal women, the influence of gonadal axis hormones on HPA axis function will be explored by comparing the two axes and the response to dexamethasone at different phases of the menstrual cycle in a subgroup of the control women. In rats, we will examine the effect of ovariectomy and replacement with gonadal steroids on the negative feedback effects of exogenous glucocorticoids at multiple levels of the HPA axis as well as the effects on stress.